Adherence of Neisseria gonorrhoeae to host cells is a complex process which is initially mediated by Type IV pili. The pilus receptor on human cells has been identified as the complement regulatory protein, CD46. Four major isoforms of CD46 are produced on all human nucleated cells. The CD46 receptor interacts directly with gonococcal pili and appears to act as a signal transducer. Our preliminary results indicate that overall levels of CD46 on epithelial cells are inversely related to gonococcal adherence. This interesting observation has lead to several questions which will be investigated in this proposal. These questions include: do CD46 isoform levels correlate to gonococcal adherence, does the strength of calcium signaling via CD46 play a role in adherence, and how does pilin variation affect interaction with CD46 isoforms and signaling? This study will determine whether certain isoforms of CD46 are responsible for pilus-mediated adherence and whether differential signal transduction events via CD46 affect levels of adherence.